Parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and 1,25(OH)2 vitamin D (1,25D) are essential for regulating calcium and phosphate homeostasis, but many aspects of their synergistic and opposing actions are unknown, especially the epigenetic regulation of Gsa expression down-stream of the PTH-receptor (PTHR1). The molecular definition of different forms of pseudohypoparathyroidism (PHP) provided major new insights into the mechanisms leading to PTH-resistant hypocalcemia and hyperphosphatemia. For example, PHP type Ia (PHP-Ia), which is caused by maternally inherited GNAS mutations, provided first evidence for the parent-specific silencing of Gsa expression in the proximal renal tubules and thus impaired PTH-dependent regulation of 1,25D production and phosphate handling; however, most details of the underlying regulatory events remain unknown. Likewise our discovery of GNAS deletions as the cause of autosomal dominant PHP type Ib (AD-PHP-Ib) and our finding that GNAS methylation changes alone can cause PTH-resistance have provided essential new insights into the epigenetic regulation of renal mineral ion handling. We now developed a mouse model of AD-PHP-Ib (DXLp/DNesp55m mice) thus allowing us to explore the mechanisms of PTH-resistance and to determine which tissues other than proximal renal tubules show imprinted Gsa expression, which may affect other endocrine systems (Aim 1). Using our large collection of DNA samples from patients with different PHP-Ib variants, we will furthermore pursue genome-wide association studies (GWAS), whole-exome sequencing, and traditional linkage studies to define novel genetic defects leading to as-of-yet undefined forms of PHP-Ib ( GNAS methylation changes) (Aim 2). We expect to determine the mechanisms responsible for PTH-resistance and Gsa silencing in PHP-Ib, to identify additional tissues with imprinted Gsa expression, to discover novel molecules that modify GNAS epigenetically or regulate events down- stream of the activated PTHR1. The resulting insights into mineral ion homeostasis may help in the treatment of common disorders such as osteoporosis and nephrolithiasis, and are likely to provide new approaches for lowering serum phosphorus levels in chronic kidney disease (CKD) thus improving outcome.